A novel therapy for breast cancer
Our genes are in constant threat of damage. To maintain genetic integrity and minimise the deleterious consequences of DNA lesions, cells have evolved sophisticated mechanisms of DNA repair collectively referred to as the DNA damage response (DDR). The DDR mechanism is highly relevant to cancer as cancer predisposing syndromes carry mutations in genes of the DDR pathways. These genes include the tumour suppressor p53 and Brca1/2, which is mutated in 50 % of familial breast and ovarian cancer cases. Recent evidence suggests that interference with different DDR pathways could be exploited as a therapeutic approach against cancer. This is exemplified through the successful use of inhibitors against the PARP1 enzyme. This enzyme repairs single-strand DNA breaks in breast cancer cells lacking BRCA1/2 and are thus deficient in homologous recombination. The EU-funded DDRESPONSE (The DNA damage response and breast cancer) consortium worked towards the development of novel treatment options using the concept of synthetic lethality. They also extended PARP inhibitors for clinical application. Through analysis of omics databases, researchers identified several DDR biomarkers associated with the BRCA1/2 status of breast cancer or predictive of the sensitivity of tumours to PARP inhibitors. They also detected epigenetic alterations in several tumours deficient in the first steps of homologous recombination. Optimised regimens of PARP inhibitors administered in combination with alkylating agents alleviated bone marrow toxicity, providing a novel way of treatment. To facilitate analysis of the effect of PARP inhibitor treatment, the consortium devoted considerable effort towards the development of novel cell-based technology. This allowed them to study DNA repair complexes in cells at the single molecule level. The work by the DDRESPONSE project culminated with the approval of the clinical formulation of the PARP inhibitor by the EMA and FDA. Clinicians can now envision personalising anti-cancer treatment regimens based on the individual patients' DNA damage response.
Keywords
Cancer, therapy, DNA damage response, BRCA1/2, PARP inhibitor
